Cell Research and Immunology, Tel Aviv University, Tel Aviv
All living cells are covered with a dense layer of sugars (glycans) indicating their essential role in life. They are found either as free forms or covalently attached to proteins or lipids (glycoconjugates). Several types of glycan families are represented on the cell surface. Altered cell surface glycosylation is a common feature of cancer cells that result from abnormal expression of glycosyltransferases. Sialic acids (Sias) are 9-carbon backbone acidic sugars found at the outermost positions of glycan chains on various glycoproteins and glycolipids on vertebrate cell surfaces and secreted glycans. Variations in Sias expression patterns are especially frequent on cancer cells and often correlate with advanced stage, progression and/or metastasis. The two major Sia forms in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form, N-glycolylneuraminic acid (Neu5Gc). Humans cannot synthesize Neu5Gc due to a specific inactivation of CMAH encoding CMP-Neu5Ac hydroxylase. Despite that, this non-human Sia metabolically incorporates in human cells as ‘self’, apparently originating from dietary Neu5Gc-rich foods (e.g., red meat).Neu5Gc is present at low levels on cell surfaces of human epithelia and endothelia, but especially accumulates in carcinomas.Consequently, it is recognized as foreign by the human immune system and result in broad anti-Neu5Gc antibodies response. Low levels of these antibodies promote weak chronic inflammation facilitating tumor progression that can be suppressed by anti-inflammatory drugs. Likewise, anti-Neu5Gc antibodies could potentially play a role in vascular inflammation disease states such as atherosclerosis. However, at higher concentrations, these antibodies suppress growth of Neu5Gc-expressing tumors. Some of these antibodies are also potential immunotherapeutics as they could promote complement- or antibody-dependent cellular cytotoxicity (CDC/ADCC) on related human cancer cells. Using a newly developed sialoglycan-microarray, a unique anti-Neu5Gc IgG was discovered as a novel carcinoma biomarker. Altogether, these findings highlight the immune recognition of incorporated dietary non-human sugar in humans.
